Mixed-type gastric carcinomas exhibit more aggressive features and indicate the histogenesis of carcinomas

Abstract

To investigate the pathobiological behaviors of gastric mixed-type (MT) carcinomas and gastric carcinogenesis, the clinicopathological characteristics of MT carcinomas were analyzed and compared with intestinal-type (IT) and diffuse-type (DT) carcinomas. The expression of Ki-67, caspase-3, p53, fragile histine triad (FHIT), maspin, extracellular matrix metalloproteinase inducer (EMMPRIN), vascular growth factor (VEGF), MUC-2, 4, 5AC and 6, CD44, E-cadherin, beta-catenin, and phosphorylated glycogen synthase kinase 3beta-ser9 (P-GSK3beta-ser9) was examined on tissue microarrays using immunohistochemistry. It was found that MT carcinomas exhibited large size, deep invasion, frequent local invasion, and lymph node metastasis in comparison with IT and DT carcinomas (p < 0.05). All the markers except MUC-5AC showed higher expression in IT than DT carcinomas (p < 0.05). The expression of maspin, EMMPRIN, VEGF, MUC-4, and membrane E-cadherin was stronger in MT intestinal than diffuse component (p < 0.05). Immunoreactivities to Ki-67, EMMPRIN, and VEGF were weaker in IT carcinoma than in the MT intestinal portion (p < 0.05), while the opposite was true for CD44, MUC-2, and MUC-6 (p < 0.05). The MT diffuse component displayed a higher expression of FHIT, VEGF, and P-GSK3beta-ser9 than DT carcinoma (p < 0.05). The accumulative survival rate of the IT carcinoma patients was higher than the other types (p < 0.05). The invasive depth, venous invasion, lymph node, peritoneal or liver metastasis, and Lauren's classification were independent prognostic factors for gastric carcinomas (p < 0.05). These findings suggested that MT carcinomas were also indicated to be more aggressive than IT and DT carcinomas. Significant differences were observed in the proliferation, apoptosis, angiogenesis, mucin secretion, and cell adhesion between IT and DT carcinomas, whereas only a few of these characteristics showed differences between the MT intestinal and diffuse parts, thus suggesting that both the MT components might originate from the stem cells with similar genetic traits, but follow different histogenic pathways.

Fig. 1

HE staining of TMA of gastric carcinomas

Fig. 2

Immunostaining of TMA of gastric carcinomas. The immunoreactivity to Ki-67 (a) and p53 (c) was localized in the nucleus; FHIT (d), caspase-3 (b), VEGF (g), maspin (e), P-GSK3β-ser⁹ (h), MUC-2 (i), MUC-5AC (k), MUC-6 (l) were seen in the cytoplasm, EMMPRIN (f) and MUC-4 (j) were seen in the cytoplasm and the plasma membrane, CD44 (m), and E-cadherin (n) in the plasma membrane; and β-catenin (o) in the nucleus, cytoplasm, and plasma membrane. These molecules were strongly expressed in the intestinal-type gastric carcinomas

Fig. 3

Relationship between prognosis of carcinoma patients' and Lauren's classification Kaplan–Meier curves of cumulative survival rate for the patients with gastric carcinoma according to Lauren's classification. IT Intestinal type, DT diffuse type, MT mixed type